tbuckley/cabot-search huggingface dataset:
CTNI-03. A PHASE I/IIA, OPEN-LABEL STUDY OF THE BRAIN-PENETRANT PARP1-SELECTIVE INHIBITOR AZD9574 AS MONOTHERAPY AND IN COMBINATION IN PATIENTS WITH ADVANCED SOLID MALIGNANCIES (CERTIS1)
Authors: Nancy Mueller, Stephen Luen, Roger Stupp, Anthony Chalmers, Baisong Huang, Massimo Squatrito, Barry Davies, Petra Hamerlik, Timothy Yap
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Currently approved Poly ADP-Ribose Polymerase (PARP) inhibitors (PARPi) selectively inhibit and trap both PARP1 and PARP2 (PARP1/2) at sites of single strand (ss) deoxyribonucleic acid (DNA) (ssDNA) damage, preventing ssDNA repair and leading to replication-dependent DNA double strand breaks. Recent data suggest that only inhibition of PARP1 is required for anti-proliferative effects, while PARP2 functions in the survival of haematopoietic stem and progenitor cells. These observations suggest that the inhibition and trapping of PARP 2 is not needed for anti-cancer effects, and may be a major driver of haematological toxicity observed. AZD9574 is a novel brain-penetrant PARPi that potently and selectively inhibits and traps PARP1, with the goal of delivering efficacious, less toxic, and more combinable PARPi. Furthermore, owing to its central nervous system penetration capability, AZD9574 may provide a new treatment option for patients with CNS malignancies or patients with brain metastases characterized by homologous recombination deficiency (HRD). METHODS This is a first-in-human modular study primarily designed to evaluate the safety and tolerability of AZD9574 as monotherapy and in combination with anti-cancer agents at increasing dose levels in patients with advanced solid malignancies, followed by expansion cohorts in specific indications. The study will also characterize the pharmacokinetics of AZD9574 and explore potential biological activity by assessing pharmacodynamic and exploratory biomarkers and anti-tumour activity. Module 1 will enrol patients with advanced breast, ovarian, pancreatic or prostate tumours harbouring homologous recombination deficiencies. Module 2 will enrol patients with isocitrate dehydrogenase (IDH)1/2 mutated glioma.
CSIG-11. HYPOXIA SIGNALING IN ACVR1-MUTANT DIFFUSE INTRINSIC PONTINE GLIOMA
Authors: Elinn Johansson, Alexander Pietras
Journal: Neuro-Oncology (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a devastating glial tumor of the brainstem primary occurring in the pediatric population. The majority of DIPG tumors (60-80%) carry lysine- to methionine point mutation in histone H3, resulting in a global reduction of H3K27 trimethylation and subsequently a unique epigenetic landscape. Moreover, a large subset of the DIPG tumors carry activating mutations in ACVR1 – the gene encoding for the BMP receptor ALK2, suggesting an oncogenic role of signaling from this receptor. Importantly potential mechanisms of ACVR1-driven oncogenesis, remain poorly understood. Similar ACVR1 mutations have been described in the rare disorder Fibrodysplasia Ossificans Progressiva (FOP), and evidence from FOP models have suggested several links between hypoxia signaling, BMP signaling, and FOP pathogenesis thus opening up for evaluation of hypoxia signaling as oncogenic effector in ACVR1mutant DIPG. Using cultured DIPG cells and adult glioma cells respectively we have tested the activity of the hypoxia pathway using a hypoxia-responsive elements (HRE)-luciferase reporter assay. Intriguingly, DIPG but not glioma cells overexpressing a mutant ACVR1 construct significantly elevated hypoxia signaling at hypoxia. Similar trends are seen when assaying neuronal stem cell cultures harboring Histone 3.1 mutations along with activated ACVR1/ALK2 signaling. Furthermore, BMP ligand stimulation resulted in a dose-dependent increase of hypoxia signaling in DIPG cells. Through querying clinical gene expression data, we found elevated hypoxia signature scores in pediatric gliomas with mutant ACVR1 as compared to those with wildtype ACVR1. Finally, ACVR1 mutations frequently co-occur with Histone 3.3 and 3.1 mutations, and the hypoxia signature score was significantly higher than baseline only in tumors also harboring these Histone 3.3 or 3.1 mutations. Together, our data suggest that hypoxia signaling is elevated downstream of ACVR1 specifically in pediatric gliomas and prompts for evaluation of hypoxia signaling as potential therapeutical target in DIPG.
TMET-11. QUINOLINATE PROMOTES ALTERNATIVELY ACTIVATED MACROPHAGE-INDUCED IMMUNE TOLERANCE IN GLIOBLASTOMA THROUGH THE NMDA/PPARG SIGNALING AXIS
Authors: Pravin Kesarwani, Shiva Kant, Yi Zhao, Antony Prabhu, Katie Buelow, C Ryan Miller, Prakash Chinnaiyan
Journal: Neuro-Oncology (2022)

Abstract There has been considerable interest in understanding the biological consequence and therapeutic implications of aberrant tryptophan metabolism in brain tumors and neurodegenerative diseases. An overwhelming majority of this work has focused on the first-step of tryptophan metabolism (kynurenine); however, this has yet to result in clinical application. Using global metabolomic profiling on &amp;gt;100 patient-derived brain tumors, we identified a 64-fold accumulation of quinolinate (QA), a downstream metabolic intermediate of the tryptophan pathway, in glioblastoma when compared to low-grade glioma. As several metabolites in the tryptophan pathway have been implicated in immune modulation, we sought to determine the impact of QA on the immune microenvironment. We identified the capacity of QA to strongly skew macrophage polarization towards the “pro-tumorigenic” M2-phenotype with suppressive properties, which recent studies suggest play a dominant role in the immune microenvironment in glioblastoma. Intriguingly, QA conferred an “M2-like” phenotype to M1 macrophages and microglia, attenuating their phagocytosis efficiency. We went on to systematically delineate a novel mechanism of macrophage polarization through QA-induced NMDA receptor activation and Foxo1/PPARg signaling. We then determined that tumor cells and host macrophages/microglia work in concert to complete both upstream and downstream metabolism of tryptophan, respectively, resulting in the accumulation of QA. We discovered a very strong positive feedback loop involving the expression of kynureninase (KYNU) in macrophages, an enzyme involved in the downstream metabolism of tryptophan and QA production, making this a lead candidate for targeting this pathway. As this represents a novel target and agents designed to inhibit this enzyme are not commercially available, we generated a Kynu-/- knockout mouse model. Intriguingly, consistent with in vitro data, tumors grown in Kynu-/- mice had a ~50% reduction in M2 macrophages, increased immune activation, decreased growth, and improved overall survival in two orthotopic glioblastoma models, supporting the therapeutic potential of targeting this pathway.
PATH-39. A 44-YEAR-OLD FEMALE WITH DICER1-MUTANT PRIMARY INTRACRANIAL SARCOMA WITH IMAGING NEAR END OF LIFE
Authors: Allison Lowman, Aleksandra Winiarz, Samuel Bobholz, Fitzgerald Kyereme, Savannah Duenweg, Dylan Coss, Elizabeth Cochran, John Charlson, Jennifer Connelly, Peter LaViolette
Journal: Neuro-Oncology (2022)

Abstract DICER1-mutant intracranial sarcomas were recently defined by WHO in the 2021 CNS tumor classifications. Currently there is a lack of literature describing the clinical nature of this disease. Here we present a case of primary intracranial sarcoma with DICER1 mutation and unknown etiology. A 44-year-old female presented with aphasia and right-sided weakness. Clinical imaging confirmed the presence of a hemorrhagic mass in the left frontal lobe and superior falx. The patient underwent two surgical resections, but a clear diagnosis was difficult to make due to heterogenous histological features and inconclusive genomic testing. The surgical samples were sent to the National Institute of Health where genetic testing indicated a DICER1 E1813D mutation with high allele frequency (97%), a TP53 mutation with high allele frequency (95%), and a high variant allele frequency NF1 splice site mutation (96%). This resulted in a diagnosis of DICER1-mutant primary intracranial sarcoma. The patient was treated with temozolomide, bevacizumab, and CPT-11. 382 days after the mass was originally identified, the patient died. A detailed analysis of the radiographic images was performed by creating T1-weighted post-contrast enhancement maps (T1C) and T2-weighted fluid attenuated inversion recovery (FLAIR) hyper-intensity maps for each timepoint. We plotted these volumes over time alongside the patient’s treatment history. Large spikes in T1C and FLAIR volume were seen 4 days prior to initiation of temozolomide and 31 days after CPT-11 treatment was ended. At the final clinical MRI, both volumes were about 4 times greater than that of the initial scan. Despite this disease’s aggressive nature, it can be difficult to accurately diagnose, due in part to very few studies investigating the clinical features of this rare tumor. With the addition of this diagnosis to WHO CNS5, future studies should examine the behavior of these tumors, aiding in earlier diagnosis and improvement of treatment guidance.
MODL-32. IMPACT OF PRDM6 ON CHROMATIN ACCESSIBILITY, GENE EXPRESSION, AND MEDULLOBLASTOMA FORMATION
Authors: Christin Schmidt, Sarah Husain, Annika Carlson, Sarah Cohen, Samantha Westelman, Linyu Wang, William Weiss, Bjoern Schwer
Journal: Neuro-Oncology (2022)

Abstract Group 4 medulloblastoma (MB) is the most common medulloblastoma subgroup and shows high incidence of metastasis and late-onset relapse. Group 4 MBs lack a unifying oncogenic driver and treatment targets, despite extensive genomic characterization. Group 4 MBs are characterized by recurrent genetic alterations in chromatin modifiers, amplification of stemness genes, and putative enhancer "hijacking" events. A substantial fraction of Group 4 MBs are characterized by enhancer hijacking through tandem duplication of SNCAIP, resulting in high expression of PRDM6, a putative transcriptional repressor and histone methyltransferase. Some PRDM6-overexpressing MBs show additional mutations in chromatin regulators and high MYCN expression. We set out to elucidate the impact and oncogenic potential of sustained PRDM6 expression in early neural stem cell populations and patient-derived medulloblastoma cells. We find that PRDM6 expression in human iPSC-derived neuroepithelial stem cells (NESCs) results in tumor growth in mice, albeit at low penetrance. Moreover, we find that PRDM6 expression in MYCN-overexpressing NESCs does not further alter tumor aggressiveness or survival in vivo. Notably, PRDM6 overexpression in the patient-derived Group 3 MYC-amplified D283-Med cell line causes significantly increased aggressiveness of tumor growth and shorter survival in mice. At the cellular level, PRDM6 localizes to the nucleus, suggesting a role in gene expression regulation. Consistent with this notion, ATAC-seq and RNA-seq analysis of PRDM6-NESCs and PRDM6-D283-Med cells reveals major changes in chromatin accessibility and gene expression, including upregulation of integrin family members and genes related to focal adhesion and extracellular matrix-receptor interaction pathways. We conclude that PRDM6 promotes tumor growth in NESCs and may play a role in tumor maintenance through interactions with the extracellular matrix and tumor microenvironment.
QLTI-22. IMPROVING BRAIN CANCER PATIENT ACCESS TO CLINICAL TRIALS ACROSS SEVEN COMMUNITY HOSPITALS, THE PROVIDENCE SOUTHERN CALIFORNIA CLINICAL RESEARCH NETWORK
Authors: Jose Carillo, Naveed Wagle, Akanksha Sharma, Tiffany Juarez, Minh Nguyen, Judy Truong, Timothy Byun, Thomas Bott, Nanor Bozoyan, David Park, Santosh Kesari
Journal: Neuro-Oncology (2022)

Abstract Despite current FDA approved treatments for glioblastoma (GBM), prognosis remains poor. The rare patient population and limited access to clinical trials are factors in this poor prognosis. Clinical trials need to increase enrollment of patients with glioblastoma and other brain cancers to more rapidly develop more effective treatments. Clinical trials are featured on NCCN guidelines, and are considered “Standard of Care” by many experts. Multiple studies have shown that access to clinical trials is associated with improved survival in GBM, however, less than 25% of patients have access or are offered clinical trials. Access to clinical trials can be even more limited in community hospitals, while a large proportion of brain tumors are treated in smaller centers. Community hospitals care for a significant number of brain tumors annually. We have developed a Clinical Research Network for Neuro-Oncology within the Providence Network involving seven hospitals to date. In the past 3 years, we have grown the number of clinical trials available in outlying cities and counties spanning a distance of 60 miles. Between the seven hospitals in our network, we have 15 clinical trials currently open for brain cancer patients, of which, 3 trials were phase I studies. Over the past 2 years, we have enrolled 104 GBM patients in clinical trials. The ability to enhance access to clinical trials by Neuro-Oncologists treating patients in the community is feasible and promising.
CSIG-25. DIFFERENTIAL YAP ACTIVITY IN HUMAN GLIOBLASTOMA TUMORSPHERES AS A POTENTIAL BIOMARKER
Authors: Eui Hyun Kim, Seok-Gu Kang
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND Hippo/YAP signaling pathway has emerged as an important driver of GBM. However, the clinical significance and expression correlation of YAP in GBM is still unknown. The purpose of this study is to elucidate the regulatory functions of YAP in response to tumorspheres (TS) in GBM. Material and METHODS In GBM-tumorspheres (TS), mRNA levels of Yap1 and TAZ were determined by RNA-Seq, and nuclear YAP1 expression level and its correlation with tumor aggressiveness were assessed through nucleus cytosolic fractionation, quantitative confocal microscopy, western blot, and TEAD4 reporter assay. Cell proliferation, stemness, and invasive properties were also measured using YAP siRNA and its inhibitor Verteporfin to reveal the effect of YAP on glioma progression. In orthotopic xenograft models, the inhibition of YAP function were tested. RESULTS All GBM-TS exhibited various phosphorylation states of YAP but no significant differences regarding the expression of YAP. Among them, TS15-88 cell line showed relatively low YAP phosphorylation in the quantified immunoblot results. Indeed, TS with reduced YAP phosphorylation was associated with aggressive cancer phenotypes. Predominant nuclear localization of YAP and binding of YAP/TAZ to TEAD in the nucleus was evident in the TS15-88 cells. The YAP knockdown (KD) by siRNA significantly resulted decrease in TS proliferation through WST and ATP assay and values were validated again through YAP inhibitor, Verteporfin (VP). YAP KD attenuated not only the invasion and stemness of TS but also caused a reduction in tumor volume and prolonged the overall survival of mice. CONCLUSION We showed alteration of gene activities by YAP and nuclear localization of YAP/TAZ complex contributes to GBM progression. Moreover, thus tuning of Yap activity results a marked suppression in aggressive phenotypes of cancer. These associations emphasize that the YAP signaling network highly suggests new therapeutic opportunities in diagnosing and treating GBM.
BIOS-01. MANAGEMENT OF OPTIC PATHWAY GLIOMA: A SYSTEMATIC REVIEW AND META-ANALYSIS
Authors: Omid Yousefi, Pouria Azami, Mohammadmahdi Sabahi, Badih Adada, Hamid Borghei-Razavi
Journal: Neuro-Oncology (2022)

Abstract In the current study, we systematically review the literature regarding the management of optic pathway glioma (OPG). This review will analyze demographics, information regarding the type of treatment, radiological and clinical (visual) outcomes, and also complications. Article selection was performed by searching PubMed, Web of Science, and Cochrane databases. Of the 105 eligible studies, a total of 4177 patients underwent different therapeutic modalities including surgery, radiotherapy, and chemotherapy. The mean age was 8.17 years and the gender ratio was 97 males per 100 females. Based on the available data, the mean follow-up was 98.6 months and 48.7% of the patients were known cases of the neurofibromatosis type1. According to the Dodge classification 1104, 941, and 1353 tumors were D1, D2, and D3, respectively. The toxicity induced by either chemo- or radiotherapy was the most common complication, followed by the ophthalmologic complications rather than visual acuity exacerbation. The pooled mortality rate was 0.12 (95%CI 0.09–0.14). Due to the unrepresentative data, improved and not changed outcomes were classified as the favorable outcome and worsened as an unfavorable. Meta-analyses were performed to determine the rate of clinical and radiological favorable outcomes. In terms of visual assessment, the pooled rate of a favorable outcome in chemotherapy, radiotherapy, and surgery was 0.74, 0.81, and 0.65, respectively and the overall pooled rate of the favorable outcome is 0.75 (95%CI 0.70–0.80). In terms of radiological assessment, the rate of a favorable outcome following chemotherapy, radiotherapy, and surgery was 0.71, 0.74, and 0.67, respectively and the overall pooled rate of the favorable outcome is 0.71 (95%CI 0.65–0.76). The subgroup analysis revealed no significant difference in the rate of clinical and radiological favorable outcomes between the different treatment modalities (P &amp;gt; 0.05). Our analyses showed that each therapeutic modality represents viable treatment options to achieve remission for these patients.
PATH-37. SPATIAL GENE EXPRESSION PROGRAMS AND PROTEIN SIGNALING MECHANISMS DRIVE MENINGIOMA EVOLUTION AND THERAPEUTIC VULNERABILITY
Authors: Calixto-Hope Lucas, Harish Vasudevan, Kyounghee Seo, William Chen, S John Liu, Abrar Choudhury, Stephen Magill, David A Solomon, Arie Perry, David Raleigh
Journal: Neuro-Oncology (2022)

Abstract Intratumor heterogeneity drives cancer evolution and resistance to therapy, but unbiased approaches to elucidate mechanisms driving intratumor heterogeneity have been lacking. Here, we integrate spatial gene expression programs and protein signaling mechanisms across 16 meningioma samples to define how intratumor heterogeneity drives molecular classification, temporal evolution, or spatial evolution of the most common primary intracranial tumor. Spatial transcriptomic analysis was performed on 38,718 regions and spatial profiling of 72 proteins comprising proliferation, stress, microenvironment, immune, or signaling modules was performed on 82 regions. DNA methylation, copy number variant, targeted gene expression profiling, targeted DNA sequencing, histologic, or immunohistochemical analyses (Ki67, H3K27me3, p16) were performed on all meningiomas to study intratumor heterogeneity in the context of pre-existing classification schemes. Primary meningioma cells, CRISPR interference, pharmacology, and 3D co-culture models were used for mechanistic and functional validation. Spatial analyses revealed significant intratumor or intertumor heterogeneity irrespective of meningioma histologic subtype or grade, DNA methylation group (Merlin-intact, Immune-enriched, Hypermitotic), copy number variant (1p loss, 1q gain, 6p gain, 9p loss, 14q loss, 22q loss), gene expression risk score, or driver mutation (NF2, CDKN2A/B, TERT promoter, BAP1, SMARCB1, ARID1A). Spatial analyses on paired histologically or molecularly distinct regions from individual meningiomas (n=4), or on paired primary and recurrent meningioma samples (n=9), revealed conserved proliferation, immune, or signaling mechanisms underlying meningioma evolution. Mechanistic and functional studies validated therapeutic vulnerabilities across spatial clusters to combinations of FDA-approved small molecules inhibiting the cell cycle (abemaciclib), epigenetic regulators (vorinostat), the DNA damage response (nariparib), MAPK signaling (erlotinib, selumetinib), or PI3K-AKT signaling (copanlisib). In summary, these data define spatial gene expression programs and protein signaling mechanisms driving meningioma evolution and therapeutic vulnerability, shedding light on past clinical failures and elucidating novel combinations of concurrent or sequential molecular therapies to treat meningiomas that are resistant to standard interventions.
NIMG-50. ASSOCIATION BETWEEN SALINITY, ACIDITY, DIFFUSIVITY, AND HYPOXIA IN HUMAN GLIOMAS USING MULTI-NUCLEAR MRI
Authors: Nicholas S Cho, Shruti Thakuria, Francesco Sanvito, Akifumi Hagiwara, Chencai Wang, Raksha Nagaraj, Jianwen Lu, Sonoko Oshima, Catalina Raymond, Timothy Cloughesy, Linda M Liau, Richard G Everson, Phioanh L Nghiemphu, Albert Lai, Benjamin Ellingson
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Sodium MRI has been recently explored in brain tumors to potentially reveal complementary information with proton MRI about the tumor microenvironment. However, there remains limited investigation combining sodium and quantitative proton MRI techniques. This pilot study explored the associations of sodium MRI with diffusion-, pH-, and hypoxia-weighted MRI biomarkers in gliomas. METHODS Eleven patients with gliomas (n=8 IDH-wild-type; n=3 IDH-mutant) who obtained sodium, anatomical, diffusion-, pH-, and hypoxia-weighted MRI were studied. All images were obtained on a 3T Siemens Prisma with a dedicated multi-nuclear head coil. Regions-of-interest were segmented on the contrast-enhancing (CE) (n=10), FLAIR (n=11), and necrotic regions (n=9). Sodium values were normalized to the mean values of the eyes. Median sodium, apparent diffusion coefficient (ADC), ADC(L) from bimodal histogram analyses, MTRasym (acidity), and R2’ (hypoxia) values were obtained. RESULTS There was increased sodium in necrosis compared to FLAIR regions (mean difference=0.24; P/i&amp;gt;&amp;lt; 0.05) and compared to CE regions (mean difference=0.17; P/i&amp;gt;=0.07). There were significant positive correlations between sodium and ADC in CE (R=0.94; P/i&amp;gt;&amp;lt; 0.0001) and FLAIR regions (ρ=0.77; P/i&amp;gt;&amp;lt; 0.01), but not in necrosis (R=0.44; P/i&amp;gt;=0.24). There was also a significant positive correlation with ADC(L) in CE regions (R=0.90; P&amp;lt; 0.001) but not in FLAIR regions (ρ=0.50; P/i&amp;gt;=0.12). Furthermore, there was a significant positive correlation between sodium and MTRasym in necrosis (R=0.74; P/i&amp;gt;&amp;lt; 0.05) and a positive trend in CE regions (R=0.55; P=0.10). There was also a negative trend between sodium and R2’ in FLAIR regions (ρ=-0.58; P/i&amp;gt;=0.11). CONCLUSIONS Because ADC and ADC(L) are inversely related to cell density, increased sodium in gliomas may reflect increased extracellular space stemming from lower cell density, as sodium concentration is higher extracellularly. Positive associations between sodium and acidity as well as negative associations between sodium and hypoxia may reflect alterations in coupled sodium-pH and sodium-hypoxia homeostasis in gliomas.